Paraneoplastic Diarrhea From Medullary Thyroid Carcinoma Resolved With Yttrium-90 Radioembolization of Liver Metastases

Abstract Medullary thyroid carcinoma (MTC) can often have an indolent course despite distant metastatic disease. Additionally, given that metastatic MTC is incurable and systemic therapies have non-negligeable toxicities, localized treatments are often favored in presence of oligo-progressive disease. Transarterial radioembolization (TARE) with yttrium-90 (Y90) has emerged as a safe and efficacious treatment for nonresectable primary and metastatic liver tumors, yet data supporting its use in metastatic MTC are limited. We present the case of a patient with hereditary MTC and large bilobar liver metastases who demonstrated tumor response and resolution of their paraneoplastic diarrhea following TARE with Y90 microspheres.


Introduction
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from the parafollicular C cells of the thyroid and represents only 1% to 2% of all thyroid cancers [1].Up to 20% of patients present with distant metastases, most commonly in the lungs, liver, and bones [2,3].Although many patients can have an indolent course despite distant disease, the 10-year survival from time of first metastasis is 10% to 40% [1].High-burden disease may also lead to paraneoplastic diarrhea, which can be debilitating and is often refractory to antimotility agents.Although incompletely understood, MTC-related diarrhea is thought to result from tumoral secretion of various substances, including calcitonin, prostaglandins, and/or serotonin [4].Somatostatin analogs achieve only modest symptom improvement, while tumor debulking, by reducing the humoral secretion of pro-diarrheal substances, is often effective in alleviating the diarrheal syndrome [2,5,6].
Liver metastases (LM) are present in up to 45% of patients with advanced MTC.Treatment is indicated when they are large, progressive, and/or symptomatic.In some instances, LM can be isolated and treated with localized therapies such as surgical resection or radiofrequency ablation.However, in most cases they are multiple and disseminated throughout the parenchyma.In this situation, chemoembolization or systemic therapy are recommended [2].Because metastatic MTC is incurable, loco-regional therapies are often favored over systemics in presence of oligo-metastatic disease.Transarterial chemoembolization (TACE) of LM from MTC has been shown to provide durable radiological and symptomatic control, although reported response rates are variable [7][8][9].While TACE with drug-eluting beads allows less systemic toxicity compared to conventional TACE, it may come with an increased risk for liver necrosis [10,11].
Over the past decade, transarterial radioembolization (TARE) with yttrium-90 (Y90) microspheres has emerged as a novel therapy for primary and secondary liver malignancies.However, limited data are available regarding its safety and efficacy for the treatment of LM from MTC.Here we report the case of a patient with hereditary MTC and multifocal LM who experienced significant radiological and symptomatic improvement following TARE with Y90.

Case Presentation
A 31-year-old female patient was diagnosed with stage IVC MTC and found to carry a germline RET C620R mutation.At initial presentation, she had innumerable lung and bilobar liver metastases, in addition to extensive cervical lymphadenopathy in the central and lateral compartments.The largest liver lesion measured 2.9 cm in segment VIII.Her baseline calcitonin level was 41 968 pg/mL (41 968 ng/L) (reference: ≤ 7.6 pg/mL; ≤7.6 ng/L), and carcinoembryonic antigen (CEA) level was 502.9 ng/mL (502.9 µg/L) (reference: 0.0-3.8ng/ mL; 0.0-3.8µg/L).She underwent a total thyroidectomy with bilateral central and lateral neck dissections in November 2019.

Diagnostic Assessment
The patient's distant disease was then watched for several years without any additional treatment, with very slow progression.In August 2023, the largest liver lesion measured 3.8 × 4.1 cm (Fig. 1A and 1B).She also had oligo-progressive disease in a dominant 1.9 cm right lower lobe lung metastasis, while the rest of the pulmonary and osseous lesions remained stable.Doubling times for calcitonin and CEA were relatively slow, at 2.7 and 3.7 years respectively.Nonetheless, the patient had significant diarrhea with associated weight loss, despite antimotility drugs, which warranted intervention.

Treatment
Although initiating a selective RET inhibitor could have been reasonable given the uncontrolled diarrhea and burdensome metastatic disease, the patient wanted to avoid long-term systemic therapy for personal reasons.It was thus decided to favor localized therapies with external beam radiation therapy (EBRT) to the oligo-progressive lung nodule and Y90-TARE of the LM.Pretreatment calcitonin level was 97 081 pg/mL (97 081 ng/L), CEA was 575 ng/mL (575 µg/L), and liver function tests were normal.
Prior to TARE, the patient underwent a planning hepatic angiography with in-room computed tomography (CT) angiography, and a technetium 99m-labeled macroaggregated albumin ( 99m Tc-MAA) injection followed by MAA singlephoton emission computed tomography (SPECT)/CT which showed multifocal tumor MAA localization and a lung shunt percentage of 3.2%.Treatment planning was performed using the partition dosimetry model.Bilobar LM were present, and the total liver volume was 1485 cc 3 with a tumor burden of 220 cc 3 (15%).The treatment plan for administration of 31 mCi of resin microspheres (Sirtex Medical) divided between the liver lobes was performed and delivered successfully.Post-Y90 SPECT/CT imaging (Fig. 1C and 1D) confirmed mean tumor dose of 150 Gy and mean normal liver dose of 18 Gy.The patient was discharged home on the same day as treatment and no short-term complications occurred.

Outcome and Follow-Up
At subsequent restaging 5 months later, the patient had significant tumor shrinkage in the treated LM: for example, the dominant segment VII/VIII mass was reduced from 3.8 cm to 2.4 cm, while another left lesion was reduced from 3.4 cm to 2.2 cm (Fig. 1E and 1F).There was also significant decrease in calcitonin of more than 50%, and in CEA by 25% (Fig. 2).Most importantly, about a month after undergoing radioembolization, the patient experienced complete resolution of her diarrhea and no longer required antimotility agents for control.Of note, she underwent EBRT to the lung 2 months after TARE, at which time the diarrhea had already resolved, suggesting that resolution of the diarrhea was achieved exclusively by the treatment of LM with Y90.Following these localized therapies, the patient's other sites of disease remained stable, so that we were able to continue with active surveillance and defer initiating systemic therapy.

Discussion
Many patients with metastatic MTC will have an indolent clinical course, with slowly progressive disease.Additionally, none of the currently available systemic therapies provide cure, and these drugs have non-negligeable potential adverse effects.Even the better tolerated RET inhibitor, selpercatinib, has a risk for hypertension and elevation of liver transaminases, among other adverse effects [12].In patients with progressive disease that could be contributing to difficult-to-control symptoms, systemic therapy may be considered; however, patients should also be offered other focal therapeutic options, especially when there is oligo-progression [2,[13][14][15].Multifocal LM are frequent in advanced MTC and are more often associated with paraneoplastic diarrhea compared with other sites of distant disease [2].Although TACE of LM has led to durable clinical responses in some patients with MTC, it has variable efficacy.Grozinsky-Glasber et al reported a 100% partial response rate in 7 patients with LM from MTC treated with TACE, with a median time to progression of 38 months [8].On the other hand, Fromingé et al treated 12 patients with TACE and reported a partial radiological tumor response in only 5/12 (42%), and improvement of diarrhea in 2/5 (40%) [7].Beyond the variable response rates, chemoembolization has several other limitations.While there is a rationale for combining the embolic particle with a chemotherapeutic agent to which the tumor is sensitive, no cytotoxic chemotherapy has been shown to provide significant benefits in metastatic MTC.Moreover, there is a risk for systemic toxicity if the chemotherapeutic agent penetrates the systemic circulation, although this is minimized with drug-eluting bead (DEB)-TACE [10,16].
Over the past 20 years, Y90-TARE has emerged as a novel therapy for primary liver carcinoma and LM from various solid tumors, with significant radiological and clinical benefit, and relatively low toxicity [17][18][19].Y90 is a pure beta emitter with limited tissue penetration and a short half-life, making it an ideal transarterial liver-targeting agent.Its mean tissue penetration is less than 2.5 mm, allowing selective high-dose irradiation of the tumor tissue while sparing the adjacent normal liver parenchyma.The Y90-labeled microspheres have a diameter of 25 to 35 micrometers, allowing them to be delivered to the tumor via the hepatic artery, without passing into the venous circulation.This is crucial, as hepatic tumors derive most of their blood supply from the arterial hepatic circulation, whereas the normal liver is predominantly fed by the portal veinous circulation.Because of their size, the microspheres will be trapped within the arteriolar vasculature surrounding the tumor, leading to selective radiation-induced tumor necrosis [20].Two Y90 microsphere products are commercially available and FDA-approved: the glass-based TheraSphere™ and the resin-based SIR-Spheres®.In hepatocellular carcinoma, some data suggest longer time to tumor progression with TARE compared to TACE [21,22].Y90-TARE allows to effectively treat patients with significant tumor burden, often in a single outpatient treatment session, as opposed to classic TACE, which requires multiple sessions.Compared with chemoembolization, TARE also tends to cause less arterial ischemia because of the smaller particle size and microembolic technique.Thus, Y90-TARE is generally well tolerated and causes limited liver injury, especially when candidates are carefully selected and advanced dosimetry is utilized [23].Optimal candidates for planned whole liver treatment should have normal baseline total bilirubin and albumin levels.Several additional measures mitigate the risk of complications: the use of cone beam CT and SPECT/CT for treatment planning, which is mandatory by international guidelines, reduces the risk of extrahepatic complications [23], while limiting the normal liver dose to less than 40 Gy and using a treatment planning software reduce the risk of hepatic decompensation.Inadequate tumor dose based on the planning phase examination, and extrahepatic microsphere deposition that cannot be mitigated with current techniques, are exclusion criteria to Y90-TARE.Potential side effects include: a mild postembolization syndrome with constitutional symptoms and abdominal pain; hepatic dysfunction, more frequent in patients with cirrhosis or those exposed to cytotoxic chemotherapy within the previous 2 months; hepatic fibrosis and/or portal hypertension; and lymphopenia [20,24,25].Rarely, penetration of the Y90 microspheres into the gastrointestinal vascular bed can lead to gastric or duodenal ulcers, while significant hepatopulmonary shunting can cause radiation-induced pneumonitis [24].Thus, an absolute contraindication to TARE is significant shunting to the lungs or gastrointestinal tract, as assessed by a pretreatment 99m Tc-MAA scan.Other relative contraindications include prior radiation therapy to the liver, and Child-Pugh class C cirrhosis.
Our case illustrates the potential of Y90 microspheres for the treatment of LM from MTC, allowing marked improvement in paraneoplastic diarrhea through tumor debulking and decrease in calcitonin levels, and delay in systemic therapy initiation.After a short-term follow-up of 5 months, no immediate adverse events had occurred in our otherwise young healthy patient with a normal baseline liver function.To the best of our knowledge, this is the first report of a case in which TARE with Y90 led to resolution of paraneoplastic diarrhea in a patient with advanced MTC.
Only one study has been published demonstrating the feasibility and efficacy of TARE with Y90-labeled microspheres for the treatment of LM from MTC [26].In this study, 8 patients with liver-dominant metastatic sporadic MTC, who had progressive and/or symptomatic disease and < 50% liver involvement, were treated with Y90-resin microspheres.Among the 6 patients who completed the 18 months of follow-up, 1 achieved a complete response, 4 had a partial response, and 1 patient had stable disease.All patients had decreases in calcitonin and CEA levels, and none of them needed to start systemic therapy after 18 months.No information was provided about paraneoplastic diarrhea improvement post-TARE.The 6 patients had only mild to moderate elevations in their liver enzymes, which were transient in most cases.However, 1 patient who was excluded from the analysis had a severe liver injury, although it had resolved 3 months later.This was the only patient in whom both hepatic lobes were treated at the same time.
In conclusion, Y90 radioembolization for LM from MTC seems to result in a favorable radiologic and biochemical response, potentially allowing to delay the initiation of systemic therapy in patients with oligo-progressive disease in the liver.Additionally, TARE seems to achieve sufficient tumor debulking to significantly reduce the secretion of pro-diarrheal humoral substances and relieve paraneoplastic diarrhea.Nevertheless, although generally well tolerated, this procedure can lead to significant hepatic and extrahepatic toxicity if patients are not carefully selected and if treatment is not planned appropriately.Additional data are needed to determine the long-term efficacy and potential complications of radioembolization of LM from MTC with Y90-labeled microspheres.

Learning Points
• Transarterial radioembolization (TARE) with yttrium-90 (Y90) microspheres is to be considered among localized therapy options for oligo-progressive and/or symptomatic liver metastases from medullary thyroid carcinoma (MTC).• Our case illustrates the efficacy of Y90 microspheres in achieving significant tumor shrinkage and reduction in calcitonin levels in a patient with large bilobar liver metastases from MTC, leading to resolution of paraneoplastic diarrhea and allowing for delay in systemic therapy initiation.

Figure 1 .
Figure 1.Liver metastases before (A and B), immediately after (C and D) and 5 months after (E and F) transarterial radioembolization with Y90-SIR-spheres.SPECT/CT images (C and D) show significant radiation emission from dominant liver metastases immediately following therapy.